Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAID's) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAID's can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAID's is the use of corticosteroids, which also produce severe adverse effects, especially when long term therapy is involved.
NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase III") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
Angiogenesis is the development of new blood vessels into a tissue or organ. Under normal conditions, angiogenesis is observed in wound healing and embryonal development. Uncontrolled angiogenesis is associated with neoplastic disease, tumor metastasis and other angiogenesis-related diseases.
Although originally developed for their anti-inflammatory properties, glucocorticoids are now recognized to have a wide variety of therapeutic uses. For example, many steroids with anti-inflammatory activity inhibit angiogenesis (U.S. Pat. No. 5,646,136).
Compounds which selectively inhibit cyclooxygenase-2 have been described in U.S. Pat. Nos. 5,380,738, 5,344,991, 5,393,790, 5,434,178, 5,474,995, 5,475,018, 5,510,368 and WO documents WO96/06840, WO95/21817, WO96/03388, WO96/03387, WO96/03392, WO96/25405, WO96/24584, WO96/03385, WO96/16934, WO95/15316, WO94/15932, WO94/27980, WO95/00501, WO94/13635, WO94/20480, and WO94/26731.
[Pyrazol-1-yl]benzenesulfonamides have been described as inhibitors of cyclooxygenase-2 and have shown promise in the treatment of inflammation, arthritis, and pain, with minimal side effects in pre-clinical and clinical trials. Their use for preventing colon cancer has been described in U.S. Pat. No. 5,760,068. However, their use for treating or preventing angiogenesis-related diseases has not been previously described.
There have been several publications describing the benefits of inhibiting angiogenesis. WO patent publication No. 96/19469 describes that COX-2 inhibitors would be useful to prevent and/or treat tumor angiogenesis and diabetic retinopathy.
The present invention is directed to the use of inhibitors of cyclooxygenase-2 for the treatment and prevention of tumor growth and metastasis that are dependent on the angiogenic process. In addition, the treatment and prevention of non-neoplastic angiogenesis-related disorders, such as retinopathies, and endometriosis is also included.